Needleless syringe provided with modular resorvoir

ABSTRACT

The technical field of the invention is that of needleless pre-filled disposable syringes, operating with a gas generator, and used for intradermal, subcutaneous and intramuscular injections, of a liquid active principle for therapeutic use in human and veterinary medicine. The inventive needleless syringes use a reservoir ( 5 ) consisting of a tube ( 6 ) closed by an upstream plug-piston ( 7 ) and a downstream plug-piston ( 8 ) between which is contained the liquid active principle. Said needleless syringes are characterized in that they are capable of injecting a variable amount of liquid active principle ( 9 ) by adapting, through displacement of the downstream plug-piston ( 8 ) in the tube ( 6 ) the volume included between the two plug-pistons ( 7,8 ) to the amount of active principle ( 9 ) to be injected.

[0001] The technical field of the invention is that of prefilled anddisposable needleless syringes functioning with a gas generator and usedfor intradermal, subcutaneous and intramuscular injections of liquidactive principle for therapeutic use in human or veterinary medicine.

[0002] For the injection devices according to the invention, a liquidactive principle consists of a more or less viscous liquid, or a mixtureof liquid, or a gel. The active principle can be a solid dissolved in asuitable solvent for injection. It can also be represented by a powderedsolid in more or less concentrated suspension in a suitable liquid. Theparticle size of the principle must be compatible with the diameter ofthe conduits in order to avoid blockages.

[0003] The needleless syringes according to the invention have theparticular feature of being able to inject a variable amount of liquidactive principle by simple modification of their reservoir, all of theirother characteristics being integrally retained.

[0004] In this way, it is possible to create, both easily and at lowercost, off-the-shelf needleless syringes which are provided with theircorrect dose of liquid active principle without having to modify theirgeometry or adapt the gas generator to the dose of liquid activeprinciple to be injected.

[0005] Needleless syringes designed to inject variable amounts of liquidactive principle already exist and have been the subject of a number ofpatents.

[0006] Mention may be made of the U.S. Pat. No. 4,913,699, for example,which describes a needleless injector intended to contain a variableamount of liquid active principle. The pressure of the liquid leavingthe injector is regulated by the difference in cross section between thethrust plunger situated upstream and a plunger stopper of smaller crosssection which is accommodated in the terminal injection channel. Thepatent WO 00/10630 also relates to a needleless injector having, interalia, the particular feature of expelling a variable amount of liquidactive principle by reducing the travel of the thrust plunger.Specifically, the reservoir of active principle, of standard size, issystematically filled to the maximum of its capacity, and the plunger,whose travel. can be reduced by a system of pressure-release vents, willensure injection of only part of the active principle enclosed in thereservoir. After the injection, some liquid active principle remains inthe bottom of the reservoir in cases where the travel of the plunger hasbeen reduced.

[0007] Finally, mention may be made of the patent application Ser. No.95/03844 which relates to a needleless injector which also has thecharacteristic of being able to inject a variable amount of activeprinciple by reducing the travel of the thrust plunger. In this case,the screwing of a button causes the displacement of the plunger at thesame time as the compression of a spring. When the plunger is at therequired position, triggering of the injector thus frees said plunger,which is propelled by the released spring.

[0008] The needleless syringes according to the invention permitinjection of a variable amount of liquid active principle by simplereadjustment of the available volume in the reservoir. This is because,whatever the amount to be injected, the reservoir takes up a constantspace within the syringe and it is only its internal volume which ismodified, without having to redefine the characteristics of the gasgenerator or of the thrust plunger in each case, and without having toredimension the different compartments of the syringe. The needlelesssyringes according to the invention thus contain the exact amount ofactive principle to be injected and fully retain their efficacy, withoutanything having to be modified, and without any active principle beingleft at the bottom of the reservoir after injection.

[0009] The subject of the present invention is a needleless syringecomprising a gas generator, a reservoir formed by a tube which is closedoff by an upstream plunger stopper and a downstream stopper betweenwhich the liquid active principle is contained, and an injection device,characterized in that said syringe is able to inject a variable amountof active principle by means of the fact that, through displacement of adownstream plunger stopper in the tube, the volume included between thetwo plunger stoppers is adapted to the amount of active principle to beinjected.

[0010] This is because the needleless syringes according to theinvention are dimensioned in such a way as to maintain their injectioncapacity despite a dimensional modification of their reservoir.Throughout the remainder of the patent, the assembly formed by the twoplunger stoppers and the active liquid principle will be called the“column of liquid”.

[0011] Advantageously, the downstream plunger stopper is at firstlocated entirely within the tube, without protruding from it.

[0012] In general, the needleless syringes according to the inventionare intended to inject liquid active principle clearly through the skinwithout loss of said principle on the skin as a result of insufficientspeed. The gas generator is thus able, in a first phase, to impart avery high speed to the liquid active principle so as to guarantee thelatter an immediate power of penetration through the skin and, in asecond phase, to maintain, as a result of almost constant pressure, asufficient speed of the liquid, so as to guarantee that the latterpasses through the skin throughout the duration of injection onceperforation has been obtained. The release of the gases by the generatorwill create a pressurized space between said generator and the upstreamplunger stopper due to the displacement of said plunger stopper. Thispressurized space, the volume of which increases up to the end of theinjection, corresponds to a gas expansion chamber. Said expansionchamber preferably does not exist when the syringe is not functioning.However, it is possible to conceive a needleless syringe according tothe invention with a free space already existing between the gasgenerator and the thrust plunger stopper. Typically, the variation inpressure over time delivered by the gas generator in the space situatedbetween said generator and the upstream plunger stopper causes, in afirst stage, the appearance of an instantaneous and very intensepressure peak, then, in a second stage, the establishment of an almostconstant pressure which is always greater than the threshold pressure ofinjection. The term “gas generator” is a generic term designating,without particular distinction, a source of energy which, when it isactivated by the user, is able to produce gases in the syringe.

[0013] The gas generator is preferably a pyrotechnic gas generatorcomprising a pyrotechnic charge and an initiation system.

[0014] The initiation system advantageously involves a percussion deviceand a primer. It is also possible to use an initiation system based on apiezoelectric crystal or a roughened area formed by two frictionsurfaces whose displacement creates an inflammation zone. Compared to areserve of pressurized gas, a pyrotechnic charge has the advantage oftaking up little space and avoids the syringe being permanentlysubjected to a high internal pressure, including in the storage phase.The pyrotechnic charge is preferably formed by the mixture of a firstpowder and a second powder, the first powder having a dynamic vivacitygreater than that of the second powder. The first powder advantageouslyhas a dynamic vivacity of greater than 8 (MPa.s)⁻¹, and the second,powder advantageously has a dynamic vivacity of less than 16 (MPa.s)⁻¹.

[0015] One way of obtaining the pressure profile permitting cleaninjection of the liquid active principle is in fact to use a pyrotechniccharge consisting of the mixture of a fast-burning powder and aslow-burning powder. A powder is described as “fast-burning” if it has ahigh dynamic vivacity, and as “slow-burning” if it has a low dynamicvivacity. Thus, the fast-burning powder makes it possible toinstantaneously create a very intense pressure peak, while theslow-burning powder, for the rest of the injection, ensures a pressurelevel which is substantially constant and sufficiently high to allow theliquid active principle to pass through the skin once perforation hasbeen obtained. This type of powder mixture is entirely suitable for theneedleless syringes according to the invention. The dynamic vivacityvalues given above are determined by the formula:${L(z)} = {{\frac{1}{P} \cdot \frac{1}{P\quad \max}}\frac{\left( {P} \right)}{t}}$

[0016] where P is the instantaneous pressure corresponding to the stateof advance z.

[0017] Pmax is the maximum pressure reached.

[0018] dP/dt is the derivative of the pressure over time$z = {\frac{P}{P\quad \max}.}$

[0019] They correspond to half-combustion values, that is to say forz=0.5 in a manometric chamber under the following conditions: chambervolume  27.8 cm³, charging density 0.036 g/cm³ powder mass    1 g.

[0020] The powder referred to as slow-burning will always have a dynamicvivacity less than that of the fast-burning powder. The two powders areadvantageously mixed loose, that is to say that the two powders are inthe state of particles which are mixed randomly, with no particularorder, the resulting powder matching the shape of the container in whichit is situated, while at the same time forming interstices between theparticles. However, it can also be envisaged that at least one of thetwo powders is present in an ordered or specific manner, for example inthe form of a bundle of strands, or in the form of a single particle ofconsiderable size, or even in agglomerated form.

[0021] The volume of the reservoir between the two plunger stoppers canpreferably vary from 0.1 ml to 2 ml depending on the injectionrequirements.

[0022] The upstream plunger stopper is advantageously situated, in afixed manner, at one of the two ends of the tube. At least one plungeris preferably lodged between the gas generator and the upstream plungerstopper. The upstream plunger stopper is preferably in contact with theplunger.

[0023] The tube is advantageously made of glass and has a thickness ofbetween 0.5 mm and 4 mm and preferably between 1.5 mm and 2.5 mm. Theglass tube must be sufficiently thick to withstand a very high internalpressure, without suffering irreversible damage such as fissuring oreven bursting open.

[0024] The two plunger stoppers are advantageously made of a deformablematerial. They are in particular obtained by molding of elastomers whichare compatible with the liquid active principle over a long duration.These elastomers can for example be chlorobutyl or bromobutyl. Theinjection device preferably comprises at least two peripheral injectionconduits which are situated outside a hollow component serving asreceptacle for the downstream plunger stopper, the depth of saidcomponent permitting clearance of the inlets of the peripheral conduitswhen said plunger stopper comes into contact with the bottom of saidhollow part.

[0025] In terms of its function, the column of liquid moves until thedownstream plunger stopper occupies the hollow component. Once blockedin said component, the plunger stopper deforms slightly so as to clearthe inlet of the lateral injection conduits and allow the activeprinciple to be expelled. The length of the tube is preferably constant.Specifically, the needleless syringes according to the invention areintended to receive a reservoir of standard size dictated by the lengthof the tube, the variations of its internal volume situated between thetwo plunger stoppers being without consequence on its externaldimensions. The plunger is advantageously lodged in a hollow body withthe same internal diameter as that of the tube and situated in itscontinuation, said hollow body and said tube being held in an envelope.

[0026] The envelope is preferably made of plastic and exerts a slightpressure on the tube so as to increase its resistance to shearing. Inthis way, the tube is able to withstand greater internal pressures.According to one alternative embodiment of the invention, the reservoircomprising the tube and the two plunger stoppers constitutes a componentwhich is autonomous of said syringe. In other words, the reservoir canbe introduced into the syringe or withdrawn at any moment. Likewise, itcan be filled separately, with the exact dose of active principle, thenintroduced into the syringe.

[0027] A free space advantageously exists between the downstream plungerstopper and the bottom of the hollow component. Thus, irrespective ofthe amount of active principle to be injected, and thereforeirrespective of the position of the downstream plunger stopper in thetube, the column of liquid will have to undergo a substantialdisplacement before the injection proper commences. The smaller theamount of product to be injected, the closer is the position of thedownstream plunger stopper to that of the upstream plunger stopper, andthe longer is the travel of the column of liquid before injection. Thepresence of a free space between the downstream plunger stopper and thebottom of the receptacle is particularly suitable for the needlelesssyringes according to the invention. Assuming that the development ofthe pressure over the course of time in the expansion chamber is adaptedto a clean injection of liquid active principle without any losses, itis imperative, for the small doses of active principle to be injected,that the free space between the downstream plunger stopper and thebottom of the receptacle is sufficiently large to allow the column ofliquid to be sufficiently accelerated before the start of the injection.This acceleration is made necessary to compensate for the decrease inpressure in the expansion chamber due to the considerable increase ofits volume, induced by the displacement of the column of liquid. Inother words, for the small amounts of active principle to be injected,the gases emitted by the gas generator will allow the column of liquidto move with an increasing speed throughout its travel. Hence, thegreater the displacement of the column, the greater the energy of itsimpact on the bottom of the receptacle because of the increasing speed,this despite the significant drop in pressure in the expansion chamber.

[0028] By way of example, the rise in pressure in the liquid for areservoir of 0.5 ml occurs at an earlier stage than for a reservoir of0.2 ml. This is explained by the fact that, for a quantity of 0.5 ml,the displacement travel is smaller than for a quantity of 0.2 ml. Theequal intensities of the maximum pressure peaks for the twoconfigurations corresponding to 0.2 ml and to 0.5 ml is justified by thefact that the kinetic energy of impact of the column of liquidcompensates for a decrease in the intrinsic thrust of the liquid, onaccount of a drop in the gas pressure due to an increase of the volumeof the space created downstream of the pyrotechnic charge.

[0029] The needleless syringes according to the invention make itpossible to inject amounts of liquid active principle by simpleadaptation of their reservoir, without having to modify their geometryor their size, or even the gas generator, and without having to addother components. They do not therefore require any redimensioning andno supplementary machining, which are sources of increased costs.

[0030] In addition, they remain the same size since the reservoir,irrespective of the amount of liquid active principle to be injected,retains its external dimensions.

[0031] Finally, adapting the reservoir remains a simple and preciseoperation, making it possible to have needleless syringes on handcarrying the exact amount of liquid active principle to be injected.

[0032] A detailed description of a preferred embodiment of the inventionis given below with reference to FIGS. 1 through 4.

[0033]FIG. 1 is a view, in partial longitudinal cross section, of aneedleless syringe which has not yet been used.

[0034]FIG. 2 is a view, in partial longitudinal cross section, of thesyringe from FIG. 1 during use, the injection not yet having started.

[0035]FIG. 3 is a view, in partial longitudinal cross section, of thesyringe from FIG. 1 at the end of use, the injection being completed.

[0036]FIG. 4 is a simplified diagram comparing the variations inpressure over the course of time, first in the free space createddownstream of the pyrotechnic charge, then in the liquid for a reservoirholding 0.5 ml of active principle, and finally in the liquid for areservoir holding 0.2 ml of active principle.

[0037] Referring to FIG. 1, a needleless syringe 1 according to theinvention comprises a pyrotechnic gas generator 2 consisting of aninitiation system and a pyrotechnic charge 3, a thrust plunger 4, areservoir 5 formed by a glass tube 6 closed off by an upstream plungerstopper 7 and a downstream plunger stopper 8 between which the liquidactive principle 9 is contained, and an injection device 10.

[0038] The initiation system involves a percussion device (not shown inFIG. 1) and a primer 12. The percussion device 11 which is triggered bya push button comprises a spring and a weight provided with a strikerpin. The weight is blocked by at least one ball wedged between saidweight and the push button, and said push button has a circular internalgroove.

[0039] The pyrotechnic charge 3 is composed of a mixture of afast-burning powder, for example, a porous powder based onnitrocellulose, and a slow-burning powder, such as anitrocellulose-based powder with heptatubular particles. The pyrotechniccharge 3 opens into a substantially cylindrical hollow body 13 which isitself continued by the tube 6 of the reservoir 5, said tube 6 havingthe same internal diameter as that of the hollow body 13. The tube 6 isin continuity with the hollow body 13 and in contact with it, these twocomponents 6 and 13 also having the same external diameter. These aretherefore perfectly aligned with one another and are maintained in thisconfiguration by an envelope 14 of plastic material exerting a slightcompression on the hollow body 13 and on the tube 6 after assembly. Theenvelope 14 starts approximately half way along the hollow body 13 andcontinues beyond the glass tube 6 with a hollow cylindrical front partwhich forms an additional internal channel adding to the internalchannel of the tube 6, said additional channel having a cross sectiongreater than that of the internal channel of the tube 6 andapproximately equal to that defined by the imaginary circle representingthe half thickness of said tube 6.

[0040] The additional channel is able to receive a hollow component 15consisting of a hollow cylindrical body closed off at one of its twoends by a plane circular surface, said component 15 being similar to ahollow cylindrical stopper. On its outer lateral surface, said hollowbody has a series of six longitudinal grooves which are parallel to oneanother and uniformly spaced.

[0041] The component 15 is engaged in the additional channel so that:

[0042] the plane circular surface of said component 15 is flush with thefree end of the front part of the envelope 14,

[0043] the outer lateral wall of the hollow cylindrical body of saidcomponent 15 is in contact with the inner lateral wall of the additionalchannel so that the longitudinal grooves form peripheral injectionconduits 20,

[0044] a passage 16 remains between the free end of the tube 6 and thefree end of the hollow cylindrical body of said component 15.

[0045] The hollow cylindrical body 13 into which the pyrotechnic charge3 opens is entirely occupied by the thrust plunger 4. The upstreamplunger stopper 7 is flush with one of the two ends of the glass tube 6and said thrust plunger 4 is in contact both with the pyrotechnic charge3 and with said upstream plunger stopper 7.

[0046] The downstream plunger stopper 8 is situated set back from theother end of the tube 6 and the liquid active principle 9 is enclosed inthe space of said tube 6 delimited by the two plunger stoppers 7, 8. Thetwo plunger stoppers 7, 8 are made of elastomer-based deformablematerial. The thrust plunger 4 is made of nondeformable material.Downstream of the downstream plunger stopper 8 there is a free space 19formed by the internal channel of that part of the tube 6 situateddownstream of the downstream plunger stopper 8 and by the internalvolume of the component 15 similar to a hollow plug, said free space 19being in communication with the outside of the syringe 1 by way of thesix peripheral injection conduits 20.

[0047] The injection device 10 comprises the front part of the envelope14 and the hollow component 15 engaged in said front part, and it thusincludes the free space 19 situated downstream of the downstream plungerstopper 8 and the six peripheral injection conduits 20.

[0048] The method of functioning of this preferred embodiment of theinvention is as follows.

[0049] The user positions the syringe 1 in such a way that its end bearsagainst the skin of the patient to be treated. A pressure applied to thepush button causes it to slide along the syringe 1 until the groovecomes level with the ball which blocks the weight. The ball, disengagingin the groove, releases the weight which, under the action of the springwhich releases, is propelled toward the primer 12, with the striker pinleading.

[0050] The primer 12 which is thus initiated causes the firing of thepyrotechnic charge 3.

[0051] Under the effect of the combustion of the fast-burning powder,the thrust plunger 4 is abruptly displaced in the internal channel ofthe hollow body 13 and of the tube 6, provoking the displacement of thecolumn of liquid. A gas expansion chamber 17 is thus created between thepyrotechnic charge 3 and the thrust plunger 4.

[0052]FIG. 2 shows the syringe 1 during use, more precisely at theinstant when the column of liquid abuts against the bottom of thereceptacle formed by the internal volume of the hollow component 15similar to a hollow plug. Comparison of FIGS. 1 and 2 shows the distancetraveled by said column with an increasing speed prior to its impact.The downstream plunger stopper 8 which occupies the whole of thereceptacle is crushed slightly, thereby freeing the passage 16 servingas an inlet to the channels 20 of the injection device 10, while theupstream plunger stopper 7 moves closer to the trapped downstreamplunger stopper 8. The liquid active principle 9 is thus expelled with apressure which is substantially decreasing, but still greater than thethreshold pressure of diffusion of the liquid after perforation of theskin, until the two plunger stoppers 7, 8 come into contact with oneanother, as is shown in FIG. 3.

[0053] During the displacement of the upstream plunger stopper 7, thevolume of the expansion chamber 17 has continually increased. At the endof injection, there is no liquid active principle left in the reservoir5 of the syringe 1.

[0054] By way of example, referring to curve A in the diagram in FIG. 4,the pressure variation, over the course of time, induced by thecombustion of the pyrotechnic charge 3 in the space created between saidcharge 3 and the plunger 4 causes the instantaneous appearance of a veryintense peak, which is followed by a phase of progressive and continuedreduction. The appearance of the very intense peak takes place afterabout 1 ms, and the phase of reduction for its part lasts for abouttwenty milliseconds. Curve B, which illustrates the pressure variationover the course of time of the liquid active principle 9 at the outletof a reservoir 5 initially containing 0.5 ml, also causes the appearanceof a very intense peak, followed by a phase of reduction. The peak iscreated a certain time after the syringe is triggered, this delaycorresponding to the travel of the column of liquid before thedownstream plunger stopper 8 arrives in abutment at the bottom of thehollow component 15.

[0055] This peak, which remains very intense, is the result of theconjunction of two phenomena:

[0056] the intrinsic thrust of the liquid 9 by the gas pressure,

[0057] the impact of the column of liquid on the bottom of the hollowcomponent 15. Since said column moves with increasing speed in thereservoir 5, the impact occurs in an acceleration phase, therebyaffording a surplus energy which promotes the expulsion of the liquid.

[0058] The phase of pressure reduction which follows is substantiallyaligned with that observed in the free space created between thepyrotechnic charge 3 and the plunger 4.

[0059] Finally, curve C which represents the pressure variation over thecourse of time of the liquid active principle 9 at the outlet of areservoir 5 initially containing 0.2 ml shows a very intense pressurepeak followed by a phase of continued reduction. The peak arrives laterthan that for curve B since the travel of the column of liquid isgreater. The peaks of curves B and C have approximately the sameintensity because the intrinsic thrust of the liquid 9 by the gaspressure—which is lower in the case of the reservoir containing 0.2 mlbecause of a drop in gas pressure due to a more considerable increase inthe volume of the space situated between the pyrotechnic charge 3 andthe plunger 4—is compensated by an increase in the kinetic energy ofimpact induced by a greater displacement of the column of liquid atincreasing speed.

[0060] The comparative diagram in FIG. 4 shows that, by simpledisplacement of the downstream plunger stopper 8, the needleless syringe1 according to the invention conserves its full efficacy, first in termsof perforation of the skin, then in terms of diffusion of the liquid 9.

1. A needleless syringe (1) comprising several elements including a gas generator, a reservoir (5) formed by a tube (6) which is closed off by an upstream plunger stopper (7) and a downstream stopper between which the liquid active principle (9) is contained, said reservoir (5) being able to have a volume which can be varied by displacement of the downstream plunger stopper (8) in said tube (6), and an injection device (10), characterized in that i) the gas generator is a pyrotechnic generator having a pyrotechnic charge (3) and an initiation system, ii) the elements of said syringe (1) are arranged in such a way as to ensure, irrespective of the amount of active principle (9) contained in the reservoir (5), the injection of all of said principle (9) through the skin, by virtue of the production, at the outlet of the injection device (10), of a pressure profile of the type consisting of an intense phase to permit penetration of the principle (9) through the skin, followed by a less intense phase to ensure its passage through the latter.
 2. The needleless syringe as claimed in claim 1, characterized in that the downstream plunger stopper (8) is at first located entirely within the tube (6).
 3. The needleless syringe as claimed in claim 1, characterized in that the pyrotechnic charge (3) is formed by the mixture of a first powder and a second powder, the first powder having a dynamic vivacity greater than that of the second powder.
 4. The needleless syringe as claimed in claim 3, characterized in that the first powder has a dynamic vivacity of greater than 8 (MPa.s)⁻¹, and the second powder has a dynamic vivacity of less than 16 (MPa.s)⁻¹.
 5. The needleless syringe as claimed in claim 1, characterized in that the volume of the reservoir (5) between the two plunger stoppers (7, 8) can vary from 0.1 ml to 2 ml.
 6. The needleless syringe as claimed in claim 1, characterized in that the upstream plunger stopper (7) is situated, in a fixed manner, at one of the two ends of the tube (6).
 7. The needleless syringe as claimed in claim 6, characterized in that at least one plunger (4) is lodged between the gas generator (2) and the upstream plunger stopper (7).
 8. The needleless syringe as claimed in claim 7, characterized in that the upstream plunger stopper (7) is in contact with the plunger (4).
 9. The needleless syringe as claimed in claim 1, characterized in that the tube (6) is made of glass and has a thickness of between 0.5 mm and 4 mm.
 10. The needleless syringe as claimed in claim 1, characterized in that the two plunger stoppers (7, 8) are made of a deformable material.
 11. The needleless syringe as claimed in claim 1, characterized in that the injection device (10) comprises at least two peripheral injection conduits (20) which are situated outside a hollow component (15) serving as receptacle for the downstream plunger stopper (8), the depth of said component (15) permitting. the clearance of the inlets of the peripheral conduits (20) when said downstream plunger stopper (8) comes into contact with the bottom of said hollow component (15).
 12. The needleless syringe as claimed in either one of claims 1 and 9, characterized in that the length of the tube (6) is constant.
 13. The needleless syringe as claimed in claim 7, characterized in that the plunger (4) is lodged in a hollow body (13) with the same internal diameter as that of the tube (6) and situated in its continuation, said hollow body (13) and said tube (6) being held in an envelope (14).
 14. The needleless syringe as claimed in claim 1, characterized in that the reservoir (5) comprising the tube (6) and the two plunger stoppers (7, 8) constitutes a component which is autonomous of said syringe (1).
 15. The needleless syringe as claimed in claim 11, characterized in that a free space (19) exists between the downstream plunger stopper (8) and the bottom of the hollow component (15). 